Detection and treatment of early glaucoma would be greatly enhanced by the development of a technique to evaluate the risks of glaucoma of an eye based on its architecture, and a more thorough understanding of the mechanisms leading to neural tissue degeneration. Our goal is to identify properties of the eye that predict susceptibility to neural tissue damage before it occurs. Early glaucomatous neural tissue degeneration is often localized to specific regions of the optic nerve head (ONH), and aging and elevated intraocular pressure (IOP) increase the risk for developing glaucoma. Our central hypothesis is that the architecture of the connective tissues of the ONH, and in particular of the lamina cribrosa within, determines the local robustness and sensitivity to IOP, and with this the regional susceptibility to neural tissue damage in early glaucoma. We have developed novel imaging techniques to obtain previously inaccessible micron-scale information of the tissues of the ONH, including detailed maps of collagen fiber alignment and the degree of stretch or relaxation of the fibers, referred to as crimp. With this information we characterize in high detail the architecture of the human lamina cribrosa and surrounding tissues at normal and elevated IOP. In Aim 1 we test the prediction that there is an association between regional susceptibility to neural tissue damage in early glaucoma and tissue architecture. In Aim 2 we test the prediction that the regions of known susceptibility to early glaucomatous damage are more sensitive to elevated IOP, in that the collagen fibers in the lamina trabeculae of these regions are the first to stretch and lose all crimp when reaching elevated IOP. We also test the hypotheses that aging is associated with changes in the tissue architecture such that older eyes are less robust than younger eyes. In Aim 3 we use numerical modeling to determine the functional relationship between age and tissue architecture and sensitivity to IOP, and test the hypotheses that the architectures of the lamina cribrosa and peripapillary sclera are major determinants of the local sensitivity to IOP, and that age- related changes in tissue architecture increase the sensitivity to IOP. This project will result in the most detailed characterization yet of the architecture of the tissues of the ONH, and of their changes with age. We will develop a comprehensive model for understanding the key elements of architecture that determine the local sensitivity to IOP, and identify characteristics of ONH architecture that are associated with the regional susceptibility to neural tissue damage in early glaucoma. This characterization will span multiple scales, from highly detailed micro-architectural features of the collagen fibers, such as fiber crimp, to the larger scale canal size and shape. This project will be an important step towards the ultimate goal of diagnosing eyes at risk of glaucoma based on their anatomy, and will provide a powerful platform for developing strategies and interventions to mitigate the risk and preserve vision, improving health.